Lithocholic acid phenocopies anti-ageing effects of calorie restriction

  • Nature. 2025 Jul;643(8070):192-200. doi: 10.1038/s41586-024-08329-5.
Qi Qu  #  1 ,  Yan Chen  #  1 ,  Yu Wang  #  1 ,  Shating Long  1 ,  Weiche Wang  1 ,  Heng-Ye Yang  1 ,  Mengqi Li  1 ,  Xiao Tian  1 ,  Xiaoyan Wei  1 ,  Yan-Hui Liu  1 ,  Shengrong Xu  1 ,  Cixiong Zhang  1 ,  Mingxia Zhu  1 ,  Sin Man Lam  2 ,  Jianfeng Wu  3 ,  Chuyu Yun  4 ,  Junjie Chen  5 ,  Shengye Xue  1 ,  Baoding Zhang  1 ,  Zhong-Zheng Zheng  1 ,  Hai-Long Piao  6 ,  Changtao Jiang  7 ,  Hao Guo  1  8 ,  Guanghou Shui  9 ,  Xianming Deng  1 ,  Chen-Song Zhang  10 ,  Sheng-Cai Lin  11
Affiliations
  • 1. State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
  • 2. LipidALL Technologies, Changzhou, China.
  • 3. Laboratory Animal Research Centre, Xiamen University, Fujian, China.
  • 4. State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, China.
  • 5. Analysis and Measurement Centre, School of Pharmaceutical Sciences, Xiamen University, Fujian, China.
  • 6. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Liaoning, China.
  • 7. Department of Physiology and Pathophysiology, Department of Immunology, School of Basic Medical Sciences, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodelling, Peking University, Beijing, China.
  • 8. Xiang'an Hospital of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 9. Institute of Genetics and Development Biology, Chinese Academy of Sciences, Beijing, China.
  • 10. State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China. [email protected].
  • 11. State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China. [email protected].
  • # Contributed equally.
PMID: 39695227 DOI: 10.1038/s41586-024-08329-5
Abstract

Calorie restriction (CR) is a dietary intervention used to promote health and longevity1,2. CR causes various metabolic changes in both the production and the circulation of metabolites1; however, it remains unclear which altered metabolites account for the physiological benefits of CR. Here we use metabolomics to analyse metabolites that exhibit changes in abundance during CR and perform subsequent functional validation. We show that lithocholic acid (LCA) is one of the metabolites that alone can recapitulate the effects of CR in mice. These effects include activation of AMP-activated protein kinase (AMPK), enhancement of muscle regeneration and rejuvenation of grip strength and running capacity. LCA also activates AMPK and induces life-extending and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster. As C. elegans and D. melanogaster are not able to synthesize LCA, these results indicate that these Animals are able to transmit the signalling effects of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes in all the three animal models. Together, we identify that administration of the CR-mediated upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans in an AMPK-dependent manner.

Products